title: Synergistic combination of valproic acid and oncolytic parvovirus H-1PV as a potential therapy against cervical and pancreatic carcinomas.
abstract: The rat parvovirus H-1PV has oncolytic and tumour-suppressive properties potentially exploitable in cancer therapy. This possibility is being explored and results are encouraging, but it is necessary to improve the oncotoxicity of the virus. Here we show that this can be achieved by co-treating cancer cells with H-1PV and histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA). We demonstrate that these agents act synergistically to kill a range of human cervical carcinoma and pancreatic carcinoma cell lines by inducing oxidative stress, DNA damage and apoptosis. Strikingly, in rat and mouse xenograft models, H-1PV/VPA co-treatment strongly inhibits tumour growth promoting complete tumour remission in all co-treated animals. At the molecular level, we found acetylation of the parvovirus nonstructural protein NS1 at residues K85 and K257 to modulate NS1-mediated transcription and cytotoxicity, both of which are enhanced by VPA treatment. These results warrant clinical evaluation of H-1PV/VPA co-treatment against cervical and pancreatic ductal carcinomas.
authors.affiliation: Infection and Cancer Program, Tumor Virology Division (F010), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Junwei
authors.initials: J
authors.lastname: Li
authors.forename: Serena
authors.initials: S
authors.lastname: Bonifati
authors.forename: Georgi
authors.initials: G
authors.lastname: Hristov
authors.forename: Tiina
authors.initials: T
authors.lastname: Marttila
authors.forename: Séverine
authors.initials: S
authors.lastname: Valmary-Degano
authors.forename: Sven
authors.initials: S
authors.lastname: Stanzel
authors.forename: Martina
authors.initials: M
authors.lastname: Schnölzer
authors.forename: Christiane
authors.initials: C
authors.lastname: Mougin
authors.forename: Marc
authors.initials: M
authors.lastname: Aprahamian
authors.forename: Svitlana P
authors.initials: SP
authors.lastname: Grekova
authors.forename: Zahari
authors.initials: Z
authors.lastname: Raykov
authors.forename: Jean
authors.initials: J
authors.lastname: Rommelaere
authors.forename: Antonio
authors.initials: A
authors.lastname: Marchini
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D050504:Oncolytic Viruses / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017992:Parvovirus / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D011923:Rats, Nude; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid
keywords: H-1PV; pancreatic ductal adenocarcinomas; parvovirus NS1 protein; valproic acid; viral oncotherapy